Kennedy's disease (KD, or spinal and bulbar muscular atrophy) affects men in mid-life and impairs motor function. Men with KD generally leave the work force early and usually require wheelchairs and other specialized aides to perform daily functions. KD is caused by a mutation in the androgen receptor (AR) gene. Mutant AR is presumed to act directly in motoneurons to cause their death, with muscle atrophy as a secondary response. Data from recently developed KD mouse models have taught us that 1) cell dysfunction rather than death underlies early losses in motor function (with motoneuronal cell death representing a late- stage event), and that 2) androgens drive expression of KD (explaining why only men develop KD). The important implication of these findings is that KD is treatable by limiting AR activity. Our novel myogenic mouse model of KD, expressing pathogenic AR only in muscle, shows the same disease phenotype as seen in other mouse models of KD, namely androgen-dependent losses in cell and motor function. Our model however offers the unexpected and novel perspective that AR may act in muscle fibers and not motoneurons to trigger KD, since the AR transgene is expressed only in skeletal muscle fibers and not motoneurons. Preliminary evidence indicates that pathogenic expression of AR in muscle has two distinct consequences: it impairs the function of motoneurons by causing defects in axonal transport and impairs muscle function by altering its contraction kinetics and overall strength. Thus, the broad goal of this project is to identify the mechanisms by which pathogenic AR expressed only in muscle fibers impairs both muscles and motoneurons, and determine how these events together cause behavioral dysfunction. To achieve this goal, we propose to assess muscle contraction kinetics and synaptic strength, parameters that have not been assessed in any KD model, using standard in vitro electrophysiological approaches. Not only will these experiments provide information about the factors causing a loss of muscle function, but they will inform us about whether synaptic dysfunction, muscle dysfunction or both triggers behavioral dysfunction. We also propose to examine the structure of neuromuscular synapses and monitor directly the transport of moving cargo in living mouse nerve, using a novel technique recently worked out for mammals. While neuromuscular synapses have been widely shown to be affected in motoneuron diseases, including amyotrophic lateral sclerosis and spinal muscular atrophy, neuromuscular synapses have yet to be examined in any KD model. Thus, these experiments are likely to yield new, important information about the critical mechanisms underlying the loss of motor function in KD. More importantly, because our model suggests that the critical pathogenic events in KD originate in muscle, our work may identify new targets in muscle for treating KD.